rs17207923

Positions:

• chr6-32069011-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365276.2(TNXB):​c.5713G>A​(p.Glu1905Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,612,862 control chromosomes in the GnomAD database, including 658 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (170 hom., cov: 32)
  • Exomes 𝑓: 0.021 (488 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0580

Genes affected

TNXB (HGNC:11976): (tenascin XB) This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing, and its deficiency has been associated with the connective tissue disorder Ehlers-Danlos syndrome. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. It is one of four genes in this cluster which have been duplicated. The duplicated copy of this gene is incomplete and is a pseudogene which is transcribed but does not encode a protein. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020450354).
• BP6: Variant 6-32069011-C-T is Benign according to our data. Variant chr6-32069011-C-T is described in ClinVar as [Benign]. Clinvar id is 261143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32069011-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.5713G>A	p.Glu1905Lys	missense_variant	16/44	ENST00000644971.2
TNXB	NM_019105.8	c.5713G>A	p.Glu1905Lys	missense_variant	16/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.5713G>A	p.Glu1905Lys	missense_variant	16/44		NM_001365276.2
TNXB	ENST00000647633.1	c.6454G>A	p.Glu2152Lys	missense_variant	17/45			P1
TNXB	ENST00000375244.7	c.5713G>A	p.Glu1905Lys	missense_variant	16/44	5

Frequencies

GnomAD3 genomes AF: 0.0377 AC: 5737 AN: 152178 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.0792

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0491

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0489

GnomAD3 exomes AF: 0.0211 AC: 5148 AN: 244330 Hom.: 117 AF XY: 0.0198 AC XY: 2642 AN XY: 133704

Gnomad AFR exome AF: 0.0800

Gnomad AMR exome AF: 0.0299

Gnomad ASJ exome AF: 0.0271

Gnomad EAS exome AF: 0.00112

Gnomad SAS exome AF: 0.00863

Gnomad FIN exome AF: 0.00246

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0317

GnomAD4 exome AF: 0.0207 AC: 30184 AN: 1460566 Hom.: 488 Cov.: 34 AF XY: 0.0199 AC XY: 14490 AN XY: 726582

Gnomad4 AFR exome AF: 0.0871

Gnomad4 AMR exome AF: 0.0330

Gnomad4 ASJ exome AF: 0.0283

Gnomad4 EAS exome AF: 0.000806

Gnomad4 SAS exome AF: 0.00876

Gnomad4 FIN exome AF: 0.00319

Gnomad4 NFE exome AF: 0.0203

Gnomad4 OTH exome AF: 0.0219

GnomAD4 genome AF: 0.0377 AC: 5735 AN: 152296 Hom.: 170 Cov.: 32 AF XY: 0.0364 AC XY: 2711 AN XY: 74460

Gnomad4 AFR AF: 0.0790

Gnomad4 AMR AF: 0.0490

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.0207

Gnomad4 OTH AF: 0.0479

Alfa AF: 0.0244 Hom.: 104

Bravo AF: 0.0436

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.0659 AC: 178

ESP6500EA AF: 0.0220 AC: 114

ExAC AF: 0.0212 AC: 2495

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 02, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.053	N
MetaRNN	Benign	0.0020	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
Vest4		0.16
ClinPred		0.065	T
GERP RS		-1.9
Varity_R		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17207923; hg19: chr6-32036788; COSMIC: COSV64490021;